Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors

Abstract

Nuclear receptors (NRs) are a family of ligand-modulated transcription factors with significant therapeutic relevance from metabolic disorders and inflammation to cancer, neurodegenerative, and psychiatric disorders. Drug discovery efforts are typically concentrated on modulating the natural ligand action within the ligand-binding pocket (LBP) in the C-terminal ligand-binding domain (LBD). Drawbacks of LBP-based strategies include physiological alterations due to disruption of ligand binding and difficulties in achieving tissue specificity. Furthermore, the lack of a "pure" and predictable mechanism of action predisposes such intervention toward drug resistance. Recent outstanding progress in our understanding of NR biology has shifted the focus of drug discovery efforts from inside to outside the LBP, affording consideration to the interaction between NRs and coactivator proteins, the interaction between NRs and DNA and the NRs' ligand-independent functions. This review encompasses such currently available NR non-LBP-based interventions and their potential application in therapy or as specific tools to probe NR biology.

Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

“…There has been little development of inhibitors that specifically target the NTD or DBD of the AR (2,43). Sadar and coworkers (44) reported on the high throughput screening-based discovery of EPI-001, a small molecule that can interact with AR-NTD to inhibit transcriptional activity and reduce tumor volume of LNCaP xenografts.…”

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

“…Therefore, targeting alternate sites on RXRα for regulating its activities could become a new strategy for RXRα-based drug discovery. Compounds that bind to alternate sites have been successfully demonstrated for other nuclear receptors [97][98][99] , including estrogen receptor, androgen receptor, VDR and T3R. Among the reported alternate sites on nuclear receptors, the coregulator-binding site is the most studied.…”

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

“…Interaction of peptides with BF-3 has been difficult to demonstrate, but more recently a group of ligand derivatives of 2-((2-phenoxyethyl)thio)-1H-benzimidazole was shown to bind specifically to the BF-3 pocket of the AR (38,48). One of these ligands is 2-((2-(2,6-dimethylphenoxy)ethyl)thio)-1H-benzo[d]imidazole (compound 49 (CPD49); Fig.…”

“…One of these ligands is 2-((2-(2,6-dimethylphenoxy)ethyl)thio)-1H-benzo[d]imidazole (compound 49 (CPD49); Fig. 6A), which exerts significant anti-androgen potency in LNCaP and enzalutamide-resistant prostate cancer cell lines (38,48). We therefore used this ligand to determine whether it would compete with the GARRPR peptides for binding to the BF-3 pocket.…”